This study is part of the three year Main Treatment Study of the NIMH Treatment of Depression Collaborative Research Program. The design compares the therapeutic efficacy of 1) two forms of psychotherapy, interpersonal psychotherapy and cognitive behavior therapy, 2) tricyclic antidepressant (imipramine) with clinical management, and 3) placebo with clinical management. Subjects will be a rigorously selected group of adult, non-psychotic, non-bipolar, non-suicidal patients with Major Depressive Disorder diagnosed by RDC criteria after extensive clinical and medical evaluation. Patients will be randomly assigned to treatment for 16 weeks with experienced psychiatrist and psychologist therapists, who have been certified and selected after 18 months of standardized training and supervision. Independent, blind clinical evaluations by trained evaluators using a piloted, standardized assessment battery will be performed at regular intervals during treatment and a 1 1/2 year follow-up period to measure clinical change in depressive and other symptoms, cognitive and social function, personality and therapy-related variables, in order to discriminate the differential effects of each therapy in this group of patients. Major data analyses will be planned with NIMH staff, conducted by the Data Processing Facility, VA Hospital, Perry Point, MD., and publications will be reviewed for approval by a Publication Board composed of the Collaborative investigators and NIMH staff.